Topical compositions and methods for epithelial-related conditions

ABSTRACT

The present invention relates to pharmaceutical, cosmetic and cosmeceutical topical compositions containing polyisoprenyl-protein inhibitor compounds and methods useful in the promotion of healthy epithelium and the treatment of epithelial-related conditions

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication No. 60/579,093 filed on Jun. 12, 2004. This application alsoclaims the benefit of priority of U.S. Provisional Patent ApplicationNo. 60/652,921 filed on Feb. 14, 2005. The entire disclosures of U.S.Provisional Patent Application No. 60/597,093 and U.S. ProvisionalPatent Application No. 60/652,921 are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical, cosmetic andcosmeceutical topical compositions containing polyisoprenyl-proteininhibitor compounds and methods useful in the promotion of healthyepithelium and the treatment of epithelial-related conditions.

BACKGROUND OF THE INVENTION

Many skin or mucosal membrane conditions or disorders result frominflammation caused by, inter alia bacteria, fungi, viruses, parasites,autoimmune disorders, allergens, environmental conditions, such asextreme temperatures, wounds, hormones and/or malignant agents. Thus,inflammation can be associated with numerous underlying conditionsranging from dry skin to infections to cancer, as well as beingsymptomatic of inflammatory disorders such as dermatitis.

Inflammation is often characterized by a strong infiltration ofleukocytes at the site of inflammation, particularly neutrophils(polymorphonuclear cells). These cells promote tissue damage byreleasing toxic substances at the vascular wall or in uninjured tissue.

Neutrophil infiltration results from amplifying cascades of cell-cellcommunication involving signal transduction proteins such as G-proteinsthat can facilitate intracellular regulation and intercellularcommunication by interacting with a wide range of different regulatoryreceptor-transducer proteins such as membrane-bound receptors. For theseinteractions to occur, many of the signal transduction proteins,including virtually all G-proteins, must first be modified by thepost-translational addition of a C15 farnesyl or C20 geranylgeranylpolyisoprenoid moiety in thioether linkage to a cysteine residue locatedat or near the carboxy terminus within a so-called CAAX box or relatedcysteine-containing sequence. Carboxy terminal polyisoprenoid cysteinesthat ultimately result from these modifications are subject tomethylesterification by a specific membrane-associatedS-adenosylmethionine-dependent polyisoprenyl-5-cysteinylmethyltransferase, Compounds that can inhibit these enzymatic reactionsor otherwise alter the interactions among polyisoprenylated signaltransduction proteins, such as G-proteins and the protein regulatorytargets with which they interact, or other intracellular signalingproteins, can be used to mitigate leukocyte responses and,theoretically, to treat inflammatory-related conditions. (see e.g.Volker et al., Methods Enzymol., 1995, 250, 216-225)

One such compound is N-acetylfarnesyl-cysteine (AFC). AFC has been shownto inhibit membrane-associated polyisoprenoid methyl transferase and toblock some neutrophil, macrophage, and platelet responses in vitro.Unfortunately, AFC requires high concentrations for efficacy and isexpected to result in generalized systemic effects and multiple sideeffects since it interferes with a central cell regulation mechanism,characteristics which would seem to preclude its use in vivo. However,because such inhibitory compounds have the potential to be highlyefficacious, there is a need in the art for compositions containingthese compounds that can act as a safe and effective antidote for skinand mucosal membrane conditions.

SUMMARY OF THE INVENTION

The invention provides a topical composition for treating or preventingan epithelial condition in a subject, including a human, in need oftreatment thereof; that includes at least one polyisoprenyl-proteininhibitor compound and a carrier.

In another embodiment, provided herein is a topical composition forpromoting healthy skin in a subject, including a human, that includes atleast one polyisoprenyl-protein inhibitor compound and a carrier.

In a further embodiment, the invention provides a topical compositionfor promoting healthy skin in a subject, including a human, thatincludes at least one polyisoprenyl-protein inhibitor compound and acarrier.

In another embodiment, provided herein, is a topical pharmaceuticalcomposition for treating or preventing an epithelial condition in asubject, including a human, in need of treatment thereof that includesat least one polyisoprenyl-protein inhibitor compound and a carrier.

In a further embodiment, the invention provides a topical cosmeticcomposition for treating or preventing an epithelial condition in asubject, including a human, in need of treatment thereof, that includesat least one polyisoprenyl-protein inhibitor compound and a carrier.

In another embodiment, provided herein is a method of treating orpreventing an epithelial-related condition, the method including thestep of topically applying onto a surface of a mammal, including ahuman, in need thereof, a pharmaceutically effective amount of acomposition including at least one polyisoprenyl-protein inhibitorcompound and a carrier.

In a further embodiment, the invention provides a method of treating orpreventing an epithelial-related condition, the method including thestep of topically applying onto a surface of a subject, including ahuman, in need thereof, a cosmetically effective amount of a compositionthat includes at least one polyisoprenyl-protein inhibitor compound anda carrier.

In another embodiment, provided herein is a method of promoting healthyskin in a subject, including a human in need thereof, the methodincluding the step of topically applying onto a surface of a subject,including a human, in need thereof, a pharmaceutically effective amountof a composition that includes at least one polyisoprenyl-proteininhibitor compound; and a carrier.

In a further embodiment, provided herein is a method of promotinghealthy skin in a subject, including a human, in need thereof, themethod including topically applying onto a surface of a subject,including a human, a cosmetically effective amount of a composition thatincludes at least one polyisoprenyl-protein inhibitor compound and acarrier.

In another embodiment, the invention provides a method of promotinghealthy skin in a subject, including a human in need thereof, the methodincluding topically applying onto a surface a cosmetically effectiveamount of a composition that includes at least one polyisoprenyl-proteininhibitor compound and a carrier.

Finally, the invention provides a method of preparing a topicalcomposition, the method including the step of admixing at least onepolyisoprenyl-protein inhibitor compound and a carrier.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Induction of edema by TPA

FIG. 2. AFC, alone, does not cause mouse ear edema.

FIG. 3. AFC inhibits TPA induced edema

FIG. 4. AFC treatment produces a dose dependent inhibition of TPAinduced MPO

FIG. 5. Histology of AFC inhibition of neutrophil infiltration

FIG. 6. AFC inhibits TPA-induced neutrophil infiltration

FIG. 7. AFC inhibition of TPA induced MPO activity at differentapplication times

FIG. 8A. AFC does not effect TPA-induced MPO activity in thecontralateral vehicle treated ear.

FIG. 8B. Dexamethasone acts to increase inhibition of TPA-induced MPOactivity in the contralateral vehicle treated ear

FIG. 8C. Indomethacin acts to increase inhibition of TPA-induced MPOactivity in the contralateral vehicle treated ear.

FIG. 9. AFC inhibits AA induced MPO.

FIG. 10. AFC reduces TPA-induced erythema

FIG. 11. Inhibition of contact dermatitis in a volunteer

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, the inventors have recognized that inventive compositionscontaining polyisoprenyl-protein inhibitor compounds such as AFC can beused effectively in topical applications to promote healthy epithelia orto treat epithelial-related disorders. These inventive compositions donot exhibit systemic effects when topically applied. Such inventivecompositions are useful for, inter cilia, their soothing, moisturizingand detergent properties, for treating cosmetic conditions and/or forgenerally promoting healthy skin. The compositions of the presentinvention may be usefully employed in cosmetic, cosmeceutical andgeneral skincare compositions as well as in pharmaceutical compositions.

The phrase “epithelia” or “epithelial” or “epithelial tissues” as usedthroughout the specification and claims is meant to include skin andmucosal membranes. Thus, the present invention offers compositionsuseful for treating a condition of the skin or a mucosal membrane, suchas, but not limited to, that of a nose, a mouth, an eye, an ear, avagina and a rectum.

The term “topical” refers to administration of an inventive compositionat, or immediately beneath, the point of application.

The phrase “topically applying” describes application onto one or moresurfaces(s) including epithelial surfaces. “Topically applying” refersto direct application to the area of the surface to be affected. Thecomposition may be applied by pouring, dropping, or spraying, if aliquid; rubbing on, if an ointment, lotion, cream, gel, or the like;dusting, if a powder; spraying, if a liquid or aerosol composition; orby any other appropriate means.

In one embodiment, the composition of the invention is a pharmaceuticalcomposition. As used herein, a “pharmaceutical composition” refers to acomposition that is employed to prevent, reduce in intensity, cure orotherwise treat a target condition or disease.

In another embodiment, the composition of the invention is a cosmeticcomposition. As used herein a “cosmetic composition’ refers to acomposition that is intended to be rubbed, poured, sprinkled, or sprayedon, introduced into, or otherwise applied to a subject or any partthereof for cleansing, beautifying, promoting attractiveness, oraltering the appearance, or an article intended for use as a componentof any such article, except that such term does not include soap.

In another embodiment, the composition of the invention is acosmeceutical composition. As used herein the term “cosmeceuticalcomposition” refers to a composition that is employed as both a cosmeticcomposition and as a pharmaceutical composition.

In another embodiment, the composition includes one or morepolyisoprenyl-protein inhibitor compounds and a carrier.

As used herein “polyisoprenyl-protein inhibitor compound” refers to acompound that can inhibit or reduce the activity of a polyisoprenylatedprotein such as a G-protein. As used herein a “G-protein” refers toheterotrimeric G-proteins that associate with receptors of the seventransmembrane domain superfamily and are involved in signal transductionand the small GTP-binding signal transduction proteins that act toregulate cellular processes, including but not limited to cytoskeletalorganization, secretion and any other protein that is subject topolyiso-prenylation, such as, but not limited to, arrestin and nuclearlaminar proteins.

Without being limited by theory, compounds known in the art to inhibitor reduce G-protein signal transducing activity act by, inter alia,effecting the ability of a G-protein to bind to an interactingregulatory target protein that is frequently, although not always,located in a cellular membrane. In order to interact with theseregulatory target proteins, G proteins and related polyisoprenylatedproteins undergo several post-translational modifications includingcovalent attachment of a farnesyl or geranylgeranyl moiety in thioetherlinkage to cysteine residues located at or in close proximity to theircarboxy termini and methylesterification of exposed terminal farnesyl-or geranylgeranyl-5-cysteinyl residues.

Inflammatory agonists stimulate the methylesterification ofpolyisoprenyl-S-cysteinyl residues of some G-proteins (Volker et al.,Methods Enzymol., 1995, 250, 216-225). Agents that inhibit thismethylesterification reaction inhibit G-protein-mediated inflammatoryresponses. Consequently, it is believed that polyisoprenyl-5-cysteinecarboxyl methyltransferase inhibitors may serve as anti-inflammatoryagents (Volker et al., Methods Enzymol., 1995, 250, 216-225).

Other preferred mechanisms for G-protein inhibition are discussed inVolker, C., Miller, R. A., McCleary, W. R., Rao, A., Poenie, M., Backer,J. M., and Stock, J. B. (1991), Effects of farnesylcysteine analogs onprotein carboxyl methylation and signal transduction. J. Biol. Chem.266, 21515-21522, herein incorporated by reference.

Non-limiting examples of polyisoprenyl-protein inhibitor compounds foruse in the composition of the present invention are described in U.S.Pat. No. 5,043,268 issued Aug. 27, 1992 to Jeffry B. Stock; U.S. Pat.No. 5,202,456, issued Apr. 13, 1993 to Robert R. Rando; U.S. Pat. No.5,705,528 issued Jan. 6, 1998 to Yoel Kloog; U.S. Pat. No. 6,096,740issued Aug. 1, 2000 to Mechoulam, et al.; U.S. Pat. No. 5,521,215 issuedMay 28, 1996 to Mechoulam; U.S. Pat. No. 5,284,867 issued Feb. 8, 1994to Mechoulam; U.S. Pat. No. 6,482,086 to Kloog issued Oct. 8, 2002; U.S.Patent Application 2003/0203942A1 published Oct. 30, 2003; U.S. Pat. No.6,372,793 issued Apr. 6, 2002 to Nazarius S. Lamango and J. Invest.Dermatol. 2003 January; 120(1):109-15 by: Halaschek-Wiener, et al. Eachof these references is incorporated by reference herein. Other compoundsinclude cannabinoids such as Δ-tetrahydrocannabinol (THC) andcannabidiol; certain unsaturated fatty acids such as linoleic acids andomega-3 fatty acids. Additional useful polyisoprenyl-protein s can befound in Volker, C. R. 1995. Carboxyl Methylation at C-terminalS-prenylcysteine residues. Ph.D. thesis, Princeton University,Princeton, N.J. It should be understood that analogs of these compoundsthat show this inhibitor activity are also useful, as are compoundshaving different structural characteristics than those described.

In one embodiment, preferred compounds include those set forth in U.S.Pat. No. 5,043,268 represented by Formula (I) and derivatives thereof.

Wherein:

R¹ is alkyl of 1 to 3 carbon atoms;R² is —COX; wherein X is —OH, —OCH₃, —NH₂, —NHR⁴, —N(R⁴)₂ or halogen;R³ is a straight or branched chain alkyl of 10 to 25 carbon atoms, astraight or branched chain alkenyl, including a polyunsaturated alkenyl,of 10 to 25 carbon atoms;R⁴ is an alkyl at least 1 to about 25 carbon atoms; and thepharmaceutically-acceptable salts and esters of these compounds thereof.

As used herein the term a “pharmaceutically-acceptable salt” refers tosalts generally that are prepared by reacting a free base with asuitable organic or inorganic acid or by reacting an acid with asuitable organic or inorganic base, wherein a basic group or an acidicgroup is present in the compound of the inventive composition.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon, optionally substituted with lower alkyl or cycloalkylsubstituents, with multiple degrees of substitution being allowed. Asused herein, “cycloalkyl” refers to an alicyclic hydrocarbon groupoptionally possessing one or more degrees of unsaturation, having fromthree to twelve carbon atoms, optionally substituted with nitrogen,oxygen, or sulfur. “Cycloalkyl” includes by way of example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and thelike

The term “straight or branched chain alkyl” as used for R³ denotesgroups including decyl, undecyl, dodedecyl, octadecyl, nonadecyl,eicosyl, heneicosyl, decosyl, tricosyl, tetracosyl, pentacosyl, and thebranched isomers thereof.

The term “straight or branched chain alkenyl” refers to a hydrocarbonmoiety having at least one carbon-carbon double bond, which can beoptionally substituted with a nitrogen-carbon double bond (includingpolyunsaturated alkenyl). Alkenyl as used herein for R³ denotes groupsincluding decenyl, undecenyl, dodecenyl, heptadecenyl, octadecenyl,nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl,tetracosenyl, pentacosenyl, the branched chain isomers thereof; andpolyunsaturated alkenes including octadec-9,12-dienyl,octadec-9,12,15-trienyl, and eicos-5,8,11,14-tetraenyl.

In a preferred embodiment, R² is —COOH. When R² is —COOH, the alkalimetal, alkaline earth metal, ammonium, and substituted ammonium saltsthereof are desired.

In another preferred embodiment, R¹ is methyl. In yet another preferredembodiment, R³ is farnesyl.

Even more preferably, R′ is methyl, R² is COOH, and R³ is farnesyl.

In yet another preferred embodiment, R′ is methyl, X is —OCH₃, and R³ isfarnesyl.

In another embodiment, the composition of the invention includes thosecompounds selected from Formula II or Formula III as set forth in U.S.Pat. No. 5,202,456.

W—Y-Q-Z  (II)

or

W—Y—Z  (III)

wherein W is a farnesyl group, a geranylgeranyl group, a substitutedfarnesyl group or a substituted geranylgeranyl group; Y is:

wherein n=1, 2, 3, 4, 5, or 6. It is understood that C₁ . . . C_(n)represents 1 to 6 carbons and that when there are two or more carbons,they are connected in a linear chain by covalent bonds. The covalentbonds may be single, double, or triple bonds. When there are three ormore carbons the bonds do not all have to be of the same type. Forexample, C₁ may be attached to C₂ by a single bond, and C₂ may beattached to C₃ by a double bond. When double or triple bonds arepresent, two or more of T_(1′), . . . T_(n′) and T_(1″ . . . T) _(n″)are eliminated. Each of T_(1′) . . . T_(n′) and T_(1″) . . .T_(n″ is independently: H, Fl, Br, —NHCOCH) ₃, —NH₂, a peptide(preferably linked to C_(n) by an amide bond; preferably of 10 or feweramino acids), an alkene group (preferably linked to C_(n) by an amidebond; preferably of 20 or fewer carbons), a polyetheleneglycol group(preferably linked to C_(n) by an amide bond), a saturated fatty acid(preferably linked to C_(n) by an amide bond; preferably of 20 or fewercarbons), or an unsaturated fatty acid (preferably linked to C_(n)through an amide bond; preferably of 20 or fewer carbons), amonosaccharide (preferably attached to C_(n) through carbon or oxygen),or a disaccharide (preferably attached to C_(n) through carbon oroxygen); and Z is —COOH or salts or esters (e.g. methyl, ethyl, orpropyl esters) thereof. Esters of —COOH, —PO₃, or —SO₃ are preferred tothe free acid because they are more readily taken up by cells, Manycells have esterases which can regenerate the free acid, which is insome cases preferred.

Regarding the farnesyl and geranylgeranyl moieties, hydrogen generallymay be replaced by fluorine, and a methyl group may generally bereplaced by a bromine. Accordingly, “substituted farnesyl group” means afarnesyl moiety in which one or more hydrogens have been replaced byfluorine or one or more methyl groups have been replaced by a bromine,and “substituted geranylgeranyl group” means a geranylgeranyl moiety inwhich one or more hydrogens have been replaced by fluorine or one ormore methyl groups have been replaced by bromine. In addition, the C═Cdouble bonds in the farnesyl or geranylgeranyl groups may be replaced bysingle bonds with the concurrent addition of hydrogens and/or halogensto the participating carbons.

In a preferred embodiment, the compounds for use in the composition ofthe invention are S-farnesylcysteine, N-acetyl-5-geranylcysteine,N-acetyl-5-farnesylcysteine (“AFC”), also referred to asN-acetyl-5-trans, trans-farnesyl-L-cysteine,N-acetyl-S-geranylgeranylcysteine (“AGGC”),S-farnesyl-2-mercaptoethanesulfonic acid, S-farnesylthioacetic acid,S-farnesylmercaptosuccinic acid, S-farnesylthiotriazole,S-farnesylthiosalicylic acid (“FTS”), S-farnesylthiosuccinic acid,2-chloro-5-farnesylaminobenzoic acid, 2-farnesyl-thionicotinicacid(“FTN”), 5-fluoro-FTS, 5-chloro-FTS, 4-chloro-FTS,S-farnesyl-methylthiosalicylic acid or combinations thereof.

In a more preferred embodiment, the inventive compositions contain oneor more of farnesylcysteine, N-acetylgeranylcysteine,N-acetylfarnesylcysteine (“AFC”), N-acetylgeranyigeranylcysteine(“AGGC”), farnesyl-2-mercaptoethanesulfonic acid, farnesylthioaceticacid, farnesylmercaptosuccinic acid, farnesylthiotriazole,farnesylthiosuccinic acid, farnesyl-thiosalicylic acid (“FTS”),2-chloro-5-farnesylaminobenzoic acid, 2-farnesyl-thionicotinicacid(“FTN”), 5-fluoro-FTS, 5-chloro-FTS, 4-chloro-FTS, andS-farnesyl-methylthiosalicylic acid.

In another preferred embodiment, AGGC and AFC are used in combination.

In a more preferred embodiment, AFC is used in the inventivecomposition.

In another embodiment, two or more polyisoprenyl-protein inhibitorcompounds are used in the inventive composition to obtain a specificpharmaceutical or cosmetic effect.

In one embodiment, polyisoprenyl-protein inhibitor compounds preventpost-translational carboxylmethylation.

In another embodiment of the present invention, polyisoprenyl-proteininhibitor compounds act by inhibiting polyisoprenyl cysteinemethyltransferase.

In another embodiment, the polyisoprenyl-protein inhibitor compound iscontained within a botanical extract. Botanical extracts may be assayedfor polyisoprenyl-protein inhibitor activity by using the methodsdescribed in the example section below. As used herein a “botanicalextract” refers to a fresh or processed (e.g. cleaned, frozen, dried,sliced, liquified) part of a single species of plant or a fresh orprocessed alga or macroscopic fungus.

In another embodiment, the polyisoprenyl-protein inhibitor compound iscontained within a bacterial extract. Bacterial extracts likewise can beassayed for polyisoprenyl-protein inhibitor activity according to themethods described in herein.

In another aspect of the present invention, the composition of thepresent invention includes a carrier. As used herein “carrier” describesa material that does not abrogate the biological activity and propertiesof the polyisoprenyl-protein inhibitor compound of the composition ofthe present invention. Carriers must be of sufficiently high purity andof sufficiently low toxicity to render them suitable for administrationto the mammal being treated. The carrier can be inert, or it can possesspharmaceutical benefits, cosmetic benefits or both.

Some non-limiting representative examples of carriers includemoisturizing agents or humectants, pH adjusting agents, a deodorantagent, fragrances, hair conditioning agents, chelating agents,preservatives, emulsifiers, thickeners, solubilizing agents, penetrationenhancers, anti-irritants, colorants and surfactants.

As used herein a “moisturizing agent” is a substance that adds orrestores moisture to the skin. Representative examples of moisturizingor humectant agents that are usable in the present invention include,without limitation, guanidine, glycolic acid and glycolate salts (e.g.ammonium salt and quaternary alkyl ammonium salt), aloe vera in any ofits variety of forms (e.g., aloe vera gel), allantoin, urazole,polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol, propyleneglycol, butylene glycol, hexylene glycol and the like, polyethyleneglycols, sugars and starches, sugar and starch derivatives (e.g.,alkoxylated glucose), hyaluronic acid, lactamide monoethanolamine,acetamide monoethanolamine and any combination thereof.

As is widely recognized in the art, since the pH of the skin is 5.5,compositions for topical skin application (to avoid irritation) shouldpreferably have a pH value of between 4.0 and 7.0, preferably between5.0 and 6.0, most preferably about 5.5 or substantially 5.5. Hence, a pHadjusting composition is typically added to bring the pH of thecomposition to the desired value. The compositions of the presentinvention therefore preferably are formulated to have a pH value thatranges between about 4.0 and about 7.0, more preferably between about5.0 and about 6.0.

Suitable pH adjusting agents include, for example, but are not limitedto, one or more adipic acids, glycines, citric acids, calciumhydroxides, magnesium aluminometasilicates, buffers or any combinationsthereof.

As used herein “deodorant agent” refers to a substance for inhibiting ormasking perspiration or other bodily odors. Representative examples ofdeodorant agents that are usable. in the context of the presentinvention include, without limitation, quaternary ammonium compoundssuch as cetyl-trimethylammonium bromide, cetyl pyridinium chloride,benzethonium chloride, diisobutyl phenoxy ethoxy ethyl dimethyl benzylammonium chloride, sodium N-lauryl sarcosine, sodium N-palmIthylsarcosine, lauroyl sarcosine, N-myristoyl glycine, potassium N-laurylsarcosine, stearyl, trimethyl ammonium chloride, sodium aluminumchlorohydroxy lactate, tricetylmethyl ammonium chloride,2,4,4′-trichloro-2′-hydroxy diphenyl ether, diaminoalkyl amides such asL-lysine hexadecyl amide, heavy metal salts of citrate, salicylate, andpiroctose, especially zinc salts, and acids thereof, heavy metal saltsof pyrithione, especially zinc pyrithione and zinc phenolsulfate. Otherdeodorant agents include, without limitation, odor absorbing materialssuch as carbonate and bicarbonate salts, e.g. as the alkali metalcarbonates and bicarbonates, ammonium and tetraalkylammonium carbonatesand bicarbonates, especially the sodium and potassium salts, or anycombination of the above. Antiperspirant agents can be incorporated inthe compositions of the present invention either in a solubilized or aparticulate form and include, for example, aluminum or zirconiumastringent salts or complexes.

As used herein “fragrance” refers to a substance having a pleasantaroma. Suitable fragrances include, but are not limited to, eucalyptusoil, camphor synthetic, peppermint oil, clove oil, lavender, chamomileand the like.

Suitable hair conditioning agents that can be used in the context of thepresent invention include, for example, one or more collagens, cationicsurfactants, modified silicones, proteins, keratins, dimethiconepolyols, quaternary ammonium compounds, halogenated quaternary ammoniumcompounds, alkoxylated carboxylic acids, alkoxylated alcohols,alkoxylated amides, sorbitan derivatives, esters, polymeric ethers,glyceryl esters, or any combinations thereof.

Chelating agents are optionally added to the compositions of the presentinvention so as to enhance the preservative or preservative system.Preferred chelating agents are mild agents, such as, for example,ethylenediaminetetraacetic acid (EDTA), EDTA derivatives, or anycombination thereof.

Suitable preservatives for use in the compositions of the presentcomposition include, without limitation, one or more alkanols, disodiumEDTA (ethylenediamine tetraacetate), EDTA salts, EDTA fatty acidconjugates, isothiazolinone, parabens such as methylparaben andpropylparaben, propylene glycols, sorbates, urea derivatives such asdiazolindinyl urea, or any combinations thereof.

“Emulsifiers” as used herein promote the formation and stabilization ofan emulsion. Suitable emulsifiers may be natural materials, finelydivided solids, or synthetic materials. Natural emulsifying agents maybe derived from either animal or vegetable sources. Those from animalsources include gelatin, egg yolk, casein, wool fat, or cholesterol.Those from vegetable sources include acacia, tragacanth, chondrus, orpectin. Vegetable sources specifically from cellulose derivativesinclude methyl cellulose and carboxymethyl cellulose to increase theviscosity. Finely divided emulsifiers include bentonite, magnesiumhydroxide, aluminum hydroxide, or magnesium trisylicate. Syntheticagents include anionic, cationic or nonionic agents. Particularly usefulare sodium lauryl sulfate, benzalkonium chloride or polyethylene glycol400 monostearate, or any combinations thereof.

“Thickeners” as used herein refer to agents that make the composition ofthe present invention dense or viscous in consistency. Suitablethickeners that can be used in the context of the present inventioninclude, for example, non-ionic water-soluble polymers such ashydroxyethylcellulose (commercially available under the TrademarkNatrosol® 250 or 350), cationic water-soluble polymers such as Polyquat37 (commercially available under the Trademark Synthalen® CN), fattyalcohols, fatty acids, anionic polymers, and their alkali salts andmixtures thereof.

As used herein “solubilizing agents” are those substances that enablesolutes to dissolve. Representative examples of solubilizing agents thatare usable in the context of the present invention include, withoutlimitation, complex-forming solubilizers such as citric acid,ethylenediamine-tetraacetate, sodium meta-phosphate, succinic acid,urea, cyclodextrin, polyvinylpyrrolidone,diethylammonium-ortho-benzoate, and micelle-forming solubilizers such asTWEEN® and spans, e.g., TWEEN 800. Other solubilizers that are usablefor the compositions of the present invention are, for example,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene n-alkylethers, n-alkyl amine n-oxides, polyoxamers, organic solvents, such asacetone, phospholipids and cyclodextrins.

A “penetration enhancer” is an agent known to accelerate the delivery ofa substance through the skin. Suitable penetration enhancers usable inthe present invention include, but are not limited to, dimethylsulfoxide(DMSO), dimethyl formamide (DMF), allantoin, urazole,N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C₁₀ MSO),polyethylene glycol monolaurate (PEGML), propylene glycol (PG),propylene glycol monolaurate (PGML), glycerol monolaurate (GML),lecithin, the 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone® from Whitby Research Incorporated, Richmond, Va.), alcohols, andthe like. The permeation enhancer may also be a vegetable oil. Such oilsinclude, for example, safflower oil, cottonseed oil and corn oil.

Additional thickeners, penetration enhancers and other adjuvants maygenerally be found in Remington's Pharmaceutical Sciences, 18^(th) or19^(th) editions, published by the Mack Publishing Company of Easton,Pa. which is incorporated herein by reference.

As used herein, an “anti-irritant” is an agent that prevents or reducessoreness, roughness, or inflammation of a bodily part. Suitableanti-irritants that can be used in the context of the present inventioninclude, for example, steroidal and non steroidal anti-inflammatoryagents or other materials such as aloe vera, chamomile, alpha-bisabolol,cola nitida extract, green tea extract, tea tree oil, licoric extract,allantoin, caffeine or other xanthines, glycyrrhizic acid and itsderivatives.

The presently known anti-irritants can be divided into water-solubleanti-irritants and water-insoluble anti-irritants. Representativeexamples of such compositions are described, for example, in U.S. Pat.No. 5,482,710 which is herein incorporated by reference.

Colorants may also be used in the compositions of the invention.Colorants include pigments or dyes or a combination thereof as thecosmetic benefit requires. Preferred pigments include, but are notlimited to, iron oxides, and titanium oxides. Suitable dyes include FD&Capproved colorants, D&C approved colorants, and those approved for usein Europe and Japan. See Marmion, D. M., Handbook of US Colorants forFood, Drugs, Cosmetics, and Medical Devices, 3rd ed, 1991 hereinincorporated by reference.

“Surfactants” as used herein are surface-active substances, such as adetergent. Suitable surfactants for use with the inventive compositionsinclude, but are not limited to, sarcosinates, glutamates, sodium alkylsulfates, ammonium alkyl sulfates, sodium alkyleth sulfates, ammoniumalkyleth sulfates, ammonium laureth-n-sulfates, sodiumlaureth-n-sulfates, isothionates, glycerylether sulfonates,sulfosuccinates and combinations thereof. More preferably, the anionicsurfactant is selected from the group consisting of sodium lauroylsarcosinate, monosodium lauroyl glutamate, sodium alkyl sulfates,ammonium alkyl sulfates, sodium alkyleth sulfates, ammonium alkylethsulfates, and combinations thereof.

In another embodiment, the inventive compositions are incorporated intoa carrier which may be in the form of a mouthwash, rinse, oral spray,suspension, dental gel, and the like. Typical oral carriers known in theart may be used in the present invention. The preferred pharmaceuticaland/or cosmetic carriers are water, ethanol, and water-ethanol mixtures.The water-ethanol mixtures are generally employed in a weight ratio fromabout 1:1 to about 20:1, preferably from about 3:1 to about 20:1, andmost preferably from about 3:1 to about 10:1, respectively. The pH valueof the oral vehicle is generally from about 4 to about 7, and preferablyfrom about 5 to about 6.5. An oral topical vehicle having a pH valuebelow about 4 is generally irritating to the oral cavity and an oralvehicle having a pH value greater than about 7 generally results in anunpleasant mouth feel.

The oral topical inventive compositions may also contain conventionaladditives normally employed in those products. Conventional additivesinclude a fluorine providing compound, a sweetening agent, a coloringagent, a humectant, a pH adjusting agent, and an emulsifier, providingthe additives do not interfere with the therapeutic or cosmeticallybeneficial properties of the inventive compositions.

The coloring agents, humectants, pH adjusting agents and emulsifiers setout above as useful in the non-oral topical inventive compositions maybe used in the oral inventive composition.

Fluorine providing compounds may be fully or slightly water soluble andare characterized by their ability to release fluoride ions or fluoridecontaining ions in water and by their lack of reaction with othercomponents in the composition. Typical fluorine providing compounds areinorganic fluoride salts such as water-soluble alkali metal, alkalineearth metal, and heavy metal salts, for example, sodium fluoride,potassium fluoride, ammonium fluoride, cuprous fluoride, zinc fluoride,stannic fluoride, stannous fluoride, barium fluoride, sodiumfluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodiummonofluorophosphate, aluminum mono- and di-fluorophosphates andfluorinated sodium calcium pyrophosphate. Alkali metal fluorides, tinfluoride and monofluorophosphates, such as sodium and stannous fluoride,sodium monofluorophosphate and mixtures thereof, are preferred.

The amount of fluorine providing compound present in the present oraltopical inventive compositions is dependent upon the type of fluorineproviding compound employed, the solubility of the fluorine compound,and the nature of the final oral inventive composition. The amount offluorine providing compound used must be a nontoxic amount. In general,the fluorine providing compound when used will be present in an amountup to about 1%, preferably from about 0.001% to about 0.1%, and mostpreferably from about 0.001% to about 0.05%, by weight of the oraltopical inventive composition.

When sweetening agents (sweeteners) are used, those sweeteners wellknown in the art, including both natural and artificial sweeteners, maybe employed. The sweetening agent used may be selected from a wide rangeof materials including water-soluble sweetening agents, water-solubleartificial sweetening agents, water-soluble sweetening agents derivedfrom naturally occurring water-soluble sweetening agents, dipeptidebased sweetening agents, and protein based sweetening agents, includingmixtures thereof

In a preferred embodiment, a pharmaceutically acceptable carrier isincluded in the composition. As used herein “a pharmaceuticallyacceptable carrier” is any substantially non-toxic carrierconventionally useable for topical administration of pharmaceuticals inwhich the polyisoprenyl-protein inhibitor compound will remain stableand bioavailable when applied directly to skin or mucosal surfaces

In another, preferred, embodiment, the compositions of the presentinvention include a cosmetically acceptable carrier. As used herein thephrase “cosmetically acceptable carrier” refers to a substantiallynon-toxic carrier, conventionally useable for the topical administrationof cosmetics, with which polyisoprenyl-protein inhibitor compounds willremain stable and bioavailable. It will be understood that cosmeticallyacceptable carriers and pharmaceutically acceptable carriers aresimilar, if not often identical, in nature.

Suitable pharmaceutically acceptable carriers include water, petroleumjelly (Vaseline™), petroleum, mineral oil, vegetable oil, animal oil,organic and inorganic waxes, such as microcrystalline, paraffin andozocerite wax, natural polymers, such as xanthanes, gelatin, cellulose,collagen, starch, or gum arabic, alcohols, polyols, and the like. Alsoincluded are the carriers described hereinabove.

In another embodiment, the pharmaceutically acceptable carrier of thecomposition of the present invention includes a sustained release ordelayed release carrier. The carrier can be any material capable ofsustained or delayed release of the polyisoprenyl-protein inhibitorcompound to provide a more efficient administration resulting in lessfrequent and/or decreased dosage of the polyisoprenyl-protein inhibitorcompound, ease of handling, and extended or delayed effects onepithelial-related conditions. Non-limiting examples of such carriersinclude liposomes, microsponges, microspheres, or microcapsules ofnatural and synthetic polymers and the like. Liposomes which may enhancethe localized delivery of the compounds of the inventive compositionwithin skin layers, may be formed from a variety of phospholipids, suchas cholesterol, stearylamines or phosphatidylcholines.

Suitable cosmetically acceptable carriers are described in the CTFAInternational Cosmetic Ingredient Dictionary and Handbook, 8th edition,edited by Wenninger and Canterbery, (The Cosmetic, Toiletry, andFragrance Association, Inc., Washington, D.C., 2000), which is hereinincorporated by reference. Also included are the carriers describedhereinabove.

In another embodiment, the compositions of the present invention canfurther include one or more additional compatible active ingredientswhich are aimed at providing the composition with anotherpharmaceutical, cosmeceutical or cosmetic effect, in addition to thatprovided by a polyisoprenyl-protein inhibitor compound of the inventivecomposition. “Compatible” as used herein means that the components ofsuch a composition are capable of being combined with each other in amanner such that there is no interaction that would substantially reducethe efficacy of the composition under ordinary use conditions.

In one embodiment, the polyisoprenyl-protein inhibitor compound of theinventive compositions is an active ingredient.

As used herein, the phrase “additional active ingredient” refers to anagent, other than a polyisoprenyl-protein inhibitor compound of theinventive composition, that exerts a pharmacological, dermatological orany other beneficial activity. It is to be understood that “otherbeneficial activity” may be one that is only perceived as such by thesubject using the inventive compositions.

In another embodiment, the polyisoprenyl-protein inhibitor compound ofthe inventive composition is a new excipient. As used herein a “newexcipient” means any inactive ingredient that is intentionally added tothe composition of the present invention and is not intended to exerttherapeutic effects at the intended dosage, although it may act toimprove product delivery. A new excipient is not fully qualified byexisting safety data with respect to the currently proposed level ofexposure, duration of exposure or route of administration. Additionalcharacteristics of new excipients can be found in the Guidance forIndustry Nonclinical Studies for the Safety Evaluation of PharmaceuticalExcipients issued by the US Food and Drug Administration Center for DrugEvaluation and Research, in May, 2005, herein incorporated by reference.

Compositions according to the present invention, which further includeone or more additional active ingredients, can therefore be furtherefficiently used, in addition to their use as a treatment for anepithelial-related condition, in the treatment of any medical, cosmeticand/or cosmeceutical condition in which applying the additional activeingredient is beneficial.

Preferred additional active ingredients according to the presentinvention include, without limitation, one or more, in any combination,of a protective agent, an emollient, an astringent, an irritant, akeratolytic, a sun screening agent, a sun tanning agent, an antibioticagent, an antifungal agent, an antiviral agent, an antiprotozoal agent,an anti-acne agent, an anesthetic agent, a steroidal anti-inflammatoryagent, a non-steroidal anti-inflammatory agent, an antipruritic agent,an anti-oxidant agent, a chemotherapeutic agent, an anti-histamineagent, a vitamin, a hormone, an anti-dandruff agent, an anti-wrinkleagent, an anti-skin atrophy agent, a sclerosing agent, a cleansingagent, a caustic agent and a hypo-pigmenting agent.

in the broadest pharmacological sense, a “protective” is any agent thatisolates the exposed surface of the skin or other membrane from harmfulor annoying stimuli. Protectives as described herein may take the formof dusting powders, adsorbents, mechanical protective agents, andplasters. Dusting powders are relatively inert and insoluble materialsthat are used to cover and protect epithelial surfaces, ulcers andwounds. Usually, these substances are finely subdivided powders thatabsorb moisture and can act as a dessicant. The absorption of skinmoisture decreases friction and also discourages certain bacterialgrowth. Some of the materials used as protective adsorbents includebentonite, insoluble salts of bismuth, boric acid, calcium carbonate,(precipitated), cellulose, corn starch, magnesium stearate, talc,titanium dioxide, zinc oxide, and zinc stearate.

Protectives also can be administered to the skin to form an adherent,continuous film that may be flexible or semi-rigid depending on thematerials and the formulations as well as the manner in which they areapplied. This material may serve several purposes including providingocclusion from the external environment, providing chemical support, andserving as vehicles for other medicaments. Mechanical protectives aregenerally either collodions or plasters. Examples include aluminumhydroxide gel, collodium, dimethicone, petrolatum gauze, absorbablegelatin film, absorbable gelatin sponge, zinc gelatin, kaolin, lanolin,anhydrous lanolin, mineral oil, mineral oil emulsion, mineral oil light,olive oil, peanut oil, petrolatum, silicones, hydrocolloids and thelike.

Preferably, protectives included in the composition of the invention aredemulcents. Demulcents are protective agents employed primarily toalleviate irritation, particularly mucous membranes or abraded tissues.They often are applied to the surface in a viscid, sticky preparationthat covers the area readily and may be medicated. A number of chemicalsubstances possess demulcent properties. These substances include thealginates, mucilages, gums, dextrins, starches, certain sugars, andpolymeric polyhydric glycols. Others include acacia, agar, benzoin,carbomer, gelatin, glycerin, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, propylene glycol, sodiumalginate, tragacanth, hydrogels and the like.

“Emollients” are generally bland, fatty or oleaginous materials whichcan be applied locally, particularly to the skin. Emollients increasethe tissue moisture content, thereby rendering the skin softer and morepliable. Increased moisture content in the skin can be achieved bypreventing water loss with an occlusive water-immiscible barrier, byincreasing the water-holding capacity in the skin with humectants, or byaltering the desquamation of the outermost skin layer, the stratumcorneum. Useful emollients include lanolin, spermaceti, mineral oil,paraffin, petrolatum, white ointment, white petroleum, yellow ointment.Also included are vegetable oils, waxes, cetyl alcohol, glycerin,hydrophilic petrolatum, isopropyl myristate, myristyl alcohol, and oleylalcohol.

“Astringents” are locally applied, generally protein precipitants, thathave such a low cell penetrability that the action essentially islimited to the cell surface and interstitial spaces. The astringentaction is accompanied by contraction and wrinkling of the tissue and byblanching. Astringents are used therapeutically to arrest hemorrhage bycoagulating the blood, to promote healing, to toughen the skin or todecrease sweating. The principal components of astringents are salts ofaluminum, zinc, manganese, iron or bismuth.

An “irritant” is a material that acts locally on the skin to induce,based on irritant concentration, hyperemia, inflammation, anddesiccation. Irritant agents include, but are not limited to, alcohol,aromatic ammonia spirits, benzoin tincture, camphor capsicum, and coaltar extracts. Preferably, the irritant is a rubefacient. As used herein“rubefacients” are agents that induce hyperemia, wherein hyperemia meansan increased amount of blood in a body part or organ. Rubefaction, whichis induced by rubefacients, results from increased circulation to aninjured area and is accompanied by a feeling of comfort, warmth, itchingand hyperesthesia.

“Keratolytics” (desquamating agents) act to remove outer layers of thestratum corneum. This is particularly useful in hyperkeratotic areas.The keratolytics include benzoyl peroxide, fluorouracil, resorcinol,salicylic acid, tretinoin, and the like.

Representative examples of sun screening agents usable in context of thepresent invention include, without limitation, p-aminobenzoic acid andits salts and derivatives thereof (ethyl, isobutyl, glyceryl esters;p-dimethylaminobenzoic acid); anthranilates (i.e., O-amino-benzoates;methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, andcyclohexenyl esters); salicylates (amyl, phenyl, octyl, benzyl, menthyl,glyceryl, and di-propylene glycol esters); cinnamic acid derivatives(menthyl and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoylpyruvate); dihydroxycinnamic acid derivatives (umbelliferone,methylumbelliferone, methylaceto-umbelliferone); trihydroxy-cinnamicacid derivatives (esculetin, methylesculetin, daphnetin, and theglucosides, esculin and daphnin); hydrocarbons (diphenylbutadiene,stilbene); dibenzylacetone and benzylacetophenone; naphtholsulfonates(sodium salts of 2-naphthol-3,6-disulfonic and of2-naphthol-6,8-disulfonic acids); di-hydroxynaphthoic acid and itssalts; o- and p-hydroxybiphenyldisulfonates; coumarin derivatives(7-hydroxy, 7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole,phenyl benzoxazole, methyl naphthoxazole, various aryl benzothiazoles);quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);quinoline derivatives (8-hydroxyquinoline salts, 2-phenylquinoline);hydroxy- or methoxy-substituted benzophenones; uric and violuric acids;tannic acid and its derivatives (e.g., hexaethylether); (butyl carbotol)(6-propyl piperonyl)ether; hydroquinone; benzophenones (oxybenzene,sulisobenzone, dioxybenzone, benzoresorcinol,2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;octocrylene; [3-(4′-methylbenzylidene boman-2-one) and4-isopropyl-di-benzoylmethane, and any combination thereof.

Representative examples of sunless tanning agents usable in the presentinvention include, without limitation, dihydroxyacetone, glyceraldehyde,indoles and their derivatives. The sunless tanning agents can be used incombination with the sunscreen agents.

The term “antibiotic agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the growth of, or todestroy bacteria, and other microorganisms, used chiefly in thetreatment of infectious diseases. Examples of antibiotic agents include,but are not limited to, Penicillin G; Methicillin; Nafcillin; Oxacillin;Cloxacillin; Dicloxacillin; Ampicillin; Amoxicillin; Ticarcillin;Carbenicillin; Mezlocillin; Azlocillin; Piperacillin; Imipenem;Aztreonam; Cephalothin; Cefaclor; Cefoxitin; Cefuroxime; Cefonicid;Cefmetazole; Cefotetan; Cefprozil; Loracarbef; Cefetamet; Cefoperazone;Cefotaxime; Ceftizoxime; Ceftriaxone; Ceftazidime; Cefepime; Cefixime;Cefpodoxime; Cefsulodin; Fleroxacin; Nalidixic acid; Norfloxacin;Ciprofloxacin; Ofloxacin; Enoxacin; Lomefloxacin; Cinoxacin;Doxycycline; Minocycline; Tetracycline; Amikacin; Gentamicin; Kanamycin;Netilmicin; Tobramycin; Streptomycin; Azithromycin; Clarithromycin;Erythromycin; Erythromycin estolate; Erythromycin ethyl succinate;Erythromycin glucoheptonate; Erythromycin lactobionate; Erythromycinstearate; Vancomycin; Teicoplanin; Chloramphenicol; Clindamycin;Trimethoprim; Sulfamethoxazole; Nitrofurantoin; Rifampin; Mupirocin;Metronidazole; Cephalexin; Roxithromycin; Co-amoxiclavuanate;combinations of Piperacillin and Tazobactam; and their various salts,acids, bases, and other derivatives. Anti-bacterial antibiotic agentsinclude, but are not limited to, penicillins, cephalosporins,carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides,glycopeptides, quinolones, tetracyclines, macrolides, andfluoroquinolones.

The term “anti-fungal agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the growth of or todestroy fungi. Anti-fungal agents include but are not limited toAmphotericin B, Candicidin, Dermostatin, Filipin, Fungichromin,Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin, Nystatin,Pecilocin, Perimycin, Azaserine, Griseofulvin, Oligomycins, Neomycin,Pyrrolnitrin, Siccanin, Tubercidin, Viridin, Butenafine, Naftifine,Terbinafine, Bifonazole, Butoconazole, Chlordantoin, Chlormidazole,Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole,Flutrimazole, Isoconazole, Ketoconazole, Lanoconazole, Miconazole,Omoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole,Tolciclate, Tolindate, Tolnaftate, Fluconawle, Itraconazole,Saperconazole, Terconazole, Acrisorcin, Amorolfine, Biphenamine,Bromosalicylchloranilide, Buclosamide, Calcium Propionate,Chlorphenesin, Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole,Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel,Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, SodiumPropionate, Sulbentine, Tenonitrozole, Triacetin, Ujothion, UndecylenicAcid, and Zinc Propionate.

The term “anti-viral agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the replication of orto destroy viruses used chiefly in the treatment of viral diseases.Anti-viral agents include, but are not limited to, Acyclovir, Cidofovir,Cytarabine, Dideoxyadenosine, Didanosine, Edoxudine, Famciclovir,Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, Lamivudine, MADU, Penciclovir, Sorivudine, Stavudine, Trifluridine, Valacyclovir,Vidarabine, Zalcitabine, Zidovudine, Acemannan, Acetylleucine,Amantadine, Amidinomycin, Delavirdine, Foscamet, Indinavir,Interferon-α, Interferon-β, Interferon-γ, Kethoxal, Lysozyme,Methisazone, Moroxydine, Nevirapine, Podophyllotoxin, Ribavirin,Rimantadine, Ritonavir2, Saquinavir, Stailimycin, Statolon,Tromantadine, Zidovudine (AZT) and Xenazoic Acid.

The term “anti-protozoal agent” as used herein means any of a group ofchemical substances having the capacity to inhibit the growth of or todestroy protozoans used chiefly in the treatment of protozoal diseases.Examples of antiprotozoal agents, without limitation includepyrimethamine (Daraprim®) sulfadiazine, and Leucovorin.

Suitable anti-acne agents of the present invention include, withoutlimitation, keratolytics, such as salicylic acid, sulfur, glycolic,pyruvic acid, resorcinol, and N-acetylcysteine; and retinoids such asretinoic acid and its derivatives (e.g., cis and trans, esters).

“Anesthetic agents” refers to agents that resulting in a reduction orloss of sensation. Non-limiting examples of anesthetic drugs that aresuitable for use in the context of the present invention includepharmaceutically acceptable salts of lidocaine, bupivacaine,chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine,dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine andphenol.

“Steroidal anti-inflammatory agent”, as used herein, refer to any one ofnumerous compounds containing a 17-carbon 4-ring system and includes thesterols, various hormones (as anabolic steroids), and glycosides.Representative examples of steroidal anti-inflammatory drugs include,without limitation, corticosteroids such as hydrocortisone,hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethasone dipropionates, clobetasolvalerate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone.flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylesters, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone, fludrocortisone, difluorosone diacetate, fluradrenoloneacetonide, medrysone, amcinafel, amcinafide, betamethasone and thebalance of its esters, chloroprednisone, chlorprednisone acetate,clocortelone, clescinolone, dichlorisone, difiurprednate, flucloronide,flunisolide, fluoromethalone, fluperolone, fluprednisolone,hydrocortisone valerate, hydrocortisone cyclopentylpropionate,hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone,beclomethasone dipropionate, triamcinolone, and mixtures thereof.

“Non-steroidal anti-inflammatory agents” refers to a large group ofagents that are aspirin-like in their action, including ibuprofen(Advil)®, naproxen sodium (Aleve)®, and acetaminophen (Tylenol)®.Additional examples of non-steroidal anti-inflammatory agents that areusable in the context of the present invention include, withoutlimitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam,and CP-14,304; disalcid, benorylate, trilisate, safapryn, solprin,diflunisal, and fendosal; acetic acid derivatives, such as diclofenac,fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac,tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic,meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acidderivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen,ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen,oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,and tiaprofenic; pyrazoles, such as phenylbutazone, oxyphenbutazone,feprazone, azapropazone, and trimethazone. Mixtures of thesenon-steroidal anti-inflammatory agents may also be employed, as well asthe dermatologically acceptable salts and esters of these agents. Forexample, etofenamate, a flufenamic acid derivative, is particularlyuseful for topical application.

“Antipruritic agents” as used herein refers to those substances thatreduce, eliminate or prevent itching. Suitable antipruritic agentsinclude, without limitation, pharmaceutically acceptable salts ofmethdilazine and trimeprazine.

“An anti-oxidant agent” as used herein refers to a substance thatinhibits oxidation or reactions promoted by oxygen or peroxides.Non-limiting examples of anti-oxidants that are usable in the context ofthe present invention include ascorbic acid (vitamin C) and its salts,ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g.,magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbylsorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherolacetate, other esters of tocopherol, butylated hydroxy benzoic acids andtheir salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid(commercially available under the tradename Trolox^(R)), gallic acid andits alkyl esters, especially propyl gallate, uric acid and its salts andalkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, glycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, gape skin/seed extracts, melanin, and rosemary extracts.

“Chemotherapetic agent” refers to chemicals useful in the treatment orcontrol of a disease. Non-limiting examples of chemotherapeutic agentsusable in context of the present invention include daunorubicin,doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin,mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycinC, 5-FU, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,irinotecan, gemcitabine cyclosporin, verapamil, valspodor, probenecid,MK571, GF120918, LY335979, biricodar, terfenadine, quinidine,pervilleine A and XR9576.

“Antihistamine agent” as used herein refers to any of various compoundsthat counteract histamine in the body and that are used for treatingallergic reactions (such as hay fever) and cold symptoms. Non-limitingexamples of antihistamines usable in context of the present inventioninclude chlorpheniramine, brompheniramine, dexchlorpheniramine,tripolidine, clemastine, diphenhydramine, promethazine, piperazines,piperidines, astemizole, loratadine and terfenadine.

“Vitamin” as used herein, refers to any of various organic substancesessential in minute quantities to the nutrition of most animals actespecially as coenzymes and precursors of coenzymes in the regulation ofmetabolic processes. Non-limiting examples of vitamins usable in contextof the present invention include vitamin A and its analogs andderivatives: retinol, retinal, retinyl palmitate, retinoic acid,tretinoin, iso-tretinoin (known collectively as retinoids), vitamin E(tocopherol and its derivatives), vitamin C (L-ascorbic acid and itsesters and other derivatives), vitamin B₃ (niacinamide and itsderivatives), alpha hydroxy acids (such as glycolic acid, lactic acid,tartaric acid, malic acid, citric acid, etc.) and beta hydroxy acids(such as salicylic acid and the like).

“Hormone” as used herein refers to natural substances produced by organsof the body that travel by blood to trigger activity in other locationsor their synthetic analogs. Suitable hormones for use in the context ofthe present invention include, but are not limited to, calciferol(Vitamin D₃) and its products, androgens, estrogens and progesterones.

“Anti-dandruff agents” as used herein refer to agents that reduce,eliminate or prevent a scurf from forming on skin, especially of thescalp, that comes off in small white or grayish scales. Exemplaryanti-dandruff ingredients usable in context of the present inventioninclude, without limitation, zinc pyrithione, shale oil and derivativesthereof such as sulfonated shale oil, selenium sulfide, sulfur;salicylic acid, coal tar, povidone-iodine, imidazoles such asketoconazole, dichlorophenyl imidazolodioxalan, clotrimazole,itraconazole, miconazole, climbazole, tioconazole, sulconazole,butoconazole, fluconazole, miconazolenitrite and any possible stereoisomers and derivatives thereof such as anthralin, piroctone olamine(Octopirox), selenium sulfide, and ciclopiroxolamine, and mixturesthereof.

“Anti-skin atrophy actives” refers to substances effective inreplenishing or rejuvenating the epidermal layer by promoting ormaintaining the natural process of desquamation. Examples of antiwrinkleand antiskin atrophy actives which can be used in context of the presentinvention include retinoic acid its prodrugs and its derivatives (e.g.,cis and trans) and analogues; salicylic acid and derivatives thereof;sulfur-containing D and L amino acids and their derivatives and salts,particularly the N-acetyl derivatives, a preferred example of which isN-acetyl L-cysteine; thiols, e.g. ethane thiol; alpha-hydroxy acids,e.g. glycolic acid, and lactic acid; phytic acid, lipoic acid;lysophosphatidic acid, and skin peel agents (e.g., phenol and the like).Sclerosing agents or sclerosants may be also employed. A “sclerosant”refers to an agent used as a chemical irritant injected into a vein insclerotherapy. The most common ones are morrhuate sodium, sodiumtetradecyl sulfate, laureth 9 and ethanolamine oleate.

Cleansing agents which may be use in the present invention includesurfactant based cleansing agents, examples of which have been listedhereinabove. Other non-surfactant-based cleansing agents known to thoseof skill in the art may also be employed.

“Caustic agents” refer to substances capable of destroying or eatingaway epithelial tissue by chemical action. Caustic agents can be used toremove dead skin cells. For example, beta-hydroxy acids, naturallyderived acids with a strong kerolytic effect, are useful for problemskin, acne or peeling.

“Hypopigmenting agents” refer to substances capable of depigmenting theskin. Suitable hypopigmenting agents include hydroquinones, mequinol,and various protease inhibitors including serine protease inhibitors,active soy and retinoic acid.

The topical compositions of the present invention can be applied locallyto the skin or mucosa and may be in any form including solutions, oils,creams, ointments, gels, lotions, shampoos, milks, cleansers,moisturizers, sprays, skin patches and the like.

In another embodiment, a polyisoprenyl-protein inhibitor compound,carrier and, optionally, additional active ingredients are formed into acomposition comprising a solution, emulsion or gel suspension.

In some embodiments, a polyisoprenyl-protein inhibitor compound, apharmaceutical or cosmetic carrier and, optionally, one or moreadditional active ingredients are in the form of a solution. A solutioncan be prepared by mixing a solute or dissolved substance (such as apolyisoprenyl-protein inhibitor compound of the invention and,optionally, one or more active ingredient(s)) uniformly throughout asolvent carrier such as water or organic solvents, such as the alcohols(e.g. ethanol or isopropanol, acetone).

In another preferred embodiment, an inventive composition comprising apolyisoprenyl-protein inhibitor compound, a carrier and other, optionalingredients can be dispersed in an emulsion. An emulsion is a two-phasesystem prepared by combining two immiscible liquid carriers, one ofwhich is disbursed uniformly throughout the other and consists ofglobules that have diameters equal to or greater than those of thelargest colloidal particles. The globule size is critical and must besuch that the system achieves maximum stability. Usually, separation ofthe two phases will not occur unless a third substance, an emulsifyingagent, is incorporated. Thus, a basic emulsion contains at least threecomponents, the two immiscible liquid carriers and the emulsifying agentas well as the polyisoprenyl-protein inhibitor compound. Most emulsionsincorporate an aqueous phase into a non-aqueous phase (or vice versa).However, it is possible to prepare emulsions that are basicallynon-aqueous, for example, anionic and cationic surfactants of thenon-aqueous immiscible system glycerin and olive oil.

Emulsifying agent carriers useful in the present invention are describedhereinabove.

When the composition of the invention is an emulsion including AFC,non-lipid-based vehicles are preferred due to the lipophilic nature ofthe compound.

In yet, another embodiment, the inhibitors of the inventive compositionscan be mixed with a gel suspension, (a semi-solid carrier) or solidcarrier to form a paste, powder, ointment, cream, lotion, hydrogel orthe like.

For example, ointments may be prepared which are in gel-suspension form.These are semi-solid preparations intended for external application tothe epithelium. Generally, ointment bases are categorized intohydrocarbon bases (oleaginous), which may use white petroleum as a base;adsorption bases (anhydrous), which might use hydrophilic petroleum oranhydrous lanolin; emulsion bases (water and oil type); emulsion bases(oil and water type); and water soluble bases, which often usepolyethylene glycol as an ointment base.

Additional compositions of the present invention usingpolyisoprenyl-protein inhibitor compounds and carriers can be readilyprepared using technology which is known in the art such as described inRemington's Pharmaceutical Sciences, 18^(th) or 19^(th) editions,published by the Mack Publishing Company of Easton, Pa.

Preferably, the compositions of the present invention include about0.01% to about 50% w/w of a polyisoprenyl-protein inhibitor compound. Ina more preferred embodiment, the amount of the polyisoprenyl-proteininhibitor compound is about 0.1% to about 20% w/w. In an even morepreferred embodiment, the amount of the polyisoprenyl-protein inhibitorcompound present in the inventive composition is preferably no more thanabout 10% w/w. In a yet, even more preferred embodiment, the amount ofthe polyisoprenyl-protein inhibitor compound is less than about 5% w/w.

According to another aspect of the present invention, there is provideda method of preparing the novel compositions described hereinabove. Theprocess generally includes admixing the at least onepolyisoprenyl-protein inhibitor compound, as described hereinabove, andthe pharmaceutically, cosmetically or cosmeceutically acceptablecarrier. In cases where additional active ingredients, as detailedabove, are present in the compositions, the process includes admixingthese ingredients together with the active ingredients and the carrier.The mixing technique utilized in the process of the present inventioncan involve any one of the known techniques for formulating topicalcompositions. A variety of exemplary formulation techniques that areusable in the process of the present invention is described, forexample, in Harry's Cosmeticology, Seventh Edition, Edited by J BWilkinson and RJ Moore, Longmann Scientific & Technical, 1982.

According to another aspect of the present invention, there is provideda method of treating a medical, cosmetic and/or cosmeceutical conditionassociated with epithelial tissues. The method is effected by topicallyapplying, a pharmaceutically, cosmetically or cosmeceutically effectiveamount of the composition of the present invention as described aboveonto a surface.

As used herein the terms “pharmaceutically effective amount”“cosmetically effective amount” or “cosmeceutically effective amount”refer to the amount of any of the compositions of the invention thatresult in a therapeutic or beneficial effect following itsadministration to a subject. The pharmaceutical, cosmeceutical orcosmetic effect can be curing, minimizing, preventing or ameliorating adisease or disorder, improving the physical appearance and aesthetics(e.g., skin hydration), or may have any other pharmaceutical,cosmeceutical or cosmetic beneficial effect. The concentration of thesubstance is selected so as to exert its pharmaceutical, cosmeceuticalor cosmetic effect, but low enough to avoid significant side effectswithin the scope and sound judgment of the skilled artisan. Theeffective amount of the composition may vary with the particularepithelial tissue being treated, the age and physical condition of thebiological subject being treated, the severity of the condition, theduration of the treatment, the nature of concurrent therapy, thespecific compound, composition or other active ingredient employed, theparticular carrier utilized, and like factors.

A skilled artisan can determine a pharmaceutically effective amount ofthe inventive compositions by determining the unit dose. As used herein,a “unit dose” refers to the amount of inventive composition required toproduce a response of 50% of maximal effect (i.e. ED₅₀). The unit dosecan be assessed by extrapolating from dose-response curves derived fromin vitro or animal model test systems.

According to this aspect of the present invention, the compositions ofthe present invention are preferably topically applied as needed. Inanother preferred embodiment, the inventive compositions are topicallyapplied between one and four times a day, more preferably twice a day(e.g., once in the morning and once in the evening). The topicalapplication of the compositions of the present invention is preferablycarried out for a time period that ranges between 1 and 30 days, morepreferably for a time period of about fourteen days. Some conditions mayrequire topical application for an indeterminate length of time.

In one embodiment, the inventive compositions are topically administeredto the epithelial surface of a subject. Non limiting examples ofepithelial surfaces onto which the compositions of the present inventioncan be applied topically include the lateral aspect of forearms, thelateral aspect of legs, elbows, feet, backhands, back, scalp, face,buttocks, the ear canal and any other skin surfaces, and any mucosalmembrane described herein. Topical application also includes applyingthe inventive compositions orally to the gingiva.

In another embodiment, the surface is a wound surface. In chronicwounds, topical application may include applying the inventivecompositions to a non-epithelial surface such as the dermis. In yetanother embodiment, the wound surface is an open wound surface. As usedherein an “open wound” is a physical trauma where the skin is lacerated,cut or punctured. As used herein, “a cut” is an injury that results in abreak or opening in the skin, “a laceration” is a jagged, irregular cut,and“a puncture” is a wound made by a pointed object (like a nail, knife,or sharp tooth).

Alternatively, the compositions may be administered to the epithelialcondition as a component of, for example, a bandage, adhesive, ortransdermal patch. In these instances, the compositions may be anintegral component of the bandage, adhesive, or transdermal patch andare thereby applied to the epithelial surface.

In one preferred embodiment, the compositions of the invention areapplied to the inside of a latex glove. When the skin touches the insideof the latex glove, the composition of the invention is applied to theskin. In this embodiment, the compositions of the invention act toprevent inflammation of the skin caused, at least in part, by beingenclosed in the glove.

As used herein the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition, substantially preventing the appearance of clinical oraesthetical symptoms of a condition, protecting from harmful or annoyingstimuli or generally promoting healthy epithelial tissue.

The term “condition” includes a variety of conditions related to skin ormucosal membranes. This term is meant to include disorders or diseases,the promotion of healthy epithelium; dry skin; and inflammation causedby any underlying mechanism or disorder.

As used herein “promotion of healthy skin” or “promoting healthy skin”,refers to providing cooling or soothing sensations, or reducingpuffiness, or promoting the appearance of reduced wrinkling orpuffiness. This phrase also refers to the subject's perception ofhis/her skin as appearing healthy or having the perception of wellnessor youth.

In another embodiment, the inventive compositions are applied to anepithelial tissue surface to protect the surface from exposure toenvironmental factors. Such factors include, but are not limited to, UVradiation, wind, hot climate extremes or cold climate extremes.

In yet another embodiment, the inventive compositions are applied toprevent wrinkles. In another embodiment, the inventive compositions areapplied to prevent photo-aging. In yet another embodiment, the inventivecomposition is administered to prevent redness or puffiness such asoccurs in diaper rash.

In another embodiment, the compositions of the present invention areused to prevent dry skin. The inventive compositions can be administeredto moisturize and protect the skin from the condition of dryness.

In another preferred embodiment, the compositions of the invention alsoare administered to treat a skin disorder that is already present, suchas dry cracked skin. In another embodiment, the inventive compositionsare administered to treat irritated skin, such as occurs with diaperrash.

In an even more preferred embodiment, the inventive compositions areapplied to treat inflammation. As used herein “inflammation” refers to aresponse to infection and injury in which cells involved indetoxification and repair are mobilized to the compromised site byinflammatory mediators. Thus, the body's response may include edema,vasodilation, fever and pain. When inflammation is localized to the skinand mucosa, erythema (redness) occurs and can be treated by thecompositions of this invention.

Inflammation can result from a wide variety of non-limiting conditions.These conditions include, but are not limited to, a) dermatitis,including, but not limited to, atopic dermatitis, medicamentosa, contactdermatitis, seborrheic, nummular dermatitis, chronic dermatitis of handsand feet, generalized exfoliative stasis, and localized scratches; b)acne, including, but not limited to, acne vulgaris, nodulocystic acne,acne fulminans, steroid acne, acne keloidalis nuchae, chloracne,pyoderma faciale, and cysts; c) folliculitis, including, but limited to,scalp folliculitis, spa pool folliculitis, oil folliculitis,pityrosporum folliculitis, and gram negative folliculitis; d)pseudofolliculitis barbae; e) chilblains; f) miliaria (prickly heat); g)rosacea including, but not limited to, tinea rosacea, steroid rosaceaand perioral dermatitis; h) eczema and psoriasis; i) bacterialinfections including, but not limited to, staphylococcal diseases,staphylococcal scalded skin syndrome, erysipelas, folliculitis,furuncles, carbuncles, paronychial infections, and erythrasma; j)surgical interventions; k) crodermatitis enteropathica; l) Sweet'sdisease; m) amyloidosis including, but not limited to, lichenamyloidosis and macular amyloidosis; n) hives, including, but notlimited to, acute generalized and chronic generalized hives and physicalhives; o) erythema annulare centrifugum and annular erythema, including,but not limited to, erythema perstans, erythema gyratum perstans,erythema gyratum repens and erythema figuratum pertans; p) bachetsyndrome including, but not limited to, uveitis, erythema nodosum,biotin response, dermatoses, pyoderma gangrenosum, erythema multiforme,aphthous ulcers, granulomatous cheilitis, dermitis herpetiformis,dermatomyositis, including juvenile DM and amyopathic DM, eosinophilicfascitis; q) insect bites and animal bites and stings, including, butnot limited to, sea bather's eruption, seaweed dermatitis, swimmersitch, scombroid fish poisoning, scabies, popular urticaria, andcutaneous larva migrans; r) fungal infections including, but not limitedto, dermatophyte infections, tinea corporis, tinea pedis, tinea unguium,tinea capitis, tinea cruris, tinea versicolor, tinea barbae, athlete'sfoot, and jock itch; s) yeast infections including, but not limited to,candidiasis, such as candida albicans, oral candida (thrush), candidalparonychia, and; t) parasites including, but not limited to, scabies,pediculosis including pediculosis capitis, pediculosis corporis, andpediculosis pubis; and v) viral infections including, but not limitedto, herpes, including simplex lesions and zoster, chicken pox(varicella) lesions, rubeola (measles) and rubella (German measles); w)vasodilation, including, but not limited to, reye's syndrome and woundhealing; x) trauma from breaks in skin; y) autoimmune conditions,including, but not limited to, cutaneous lupus erythematosus; z) bullousdisease, including, but not limited to, phemphigus; aa) adverse drugreactions; bb) a immune hyperreactivity conditions including, but notlimited to, polymorphic light eruption, photosensitivity, dermographism,and erythema multiforme; cc) cancer; dd) burns; ee) wounds; ff) cysts,gg) hidradinitis suppurativa hh) cellulitis.

While the compositions discussed hereinbefore do not necessarily treatthe underlying disease state that may give rise to the inflamedconditions, the inventive compositions are useful for diminishing oralleviating the inflammation of the skin.

Additionally, the compositions may be used in anorectal creams andsuppositories to treat conditions such as a pruritus, proctitis, analfissures, and hemorrhoids.

The topical therapeutic compositions may further be used inophthalmological preparations to treat inflammation such as that whichresults from corneal ulcers, radialkeratotomy, corneal transplants,epikeratophakia and other surgically induced wounds in the eye.

The inventive compositions also may be used orally in the form of amouth wash or spray to protect and accelerate the healing of injuredoral tissue such as mouth sores, burns or gingivitis.

The present invention described hereinabove has both human andveterinary utility. The term “subject” as used herein includes animalsof, avian, reptilian or mammalian origin. Preferably, subjects aremammals. Even more preferably, subjects are human.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges which may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describedthe methods and/or materials in connection with which the publicationsare cited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural references unlessthe context clearly dictates otherwise. All technical and scientificterms used herein have the same meaning.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Dermal inflammation results in edema, erythema and tenderness. Dermalinflammation has the advantage of being rapidly induced, easily observedand rapidly measured. In addition, there are a number of factorsinvolved in eliciting an inflammatory response. Epidermal keratinocytes,which respond directly to a irritant because of their superficiallocation, also, release inflammatory mediators. These mediators can actdirectly (1) to attract inflammatory cells to the endothelium of thedermal venules or (2) to guide inflammatory cells through the dermis tothe site of inflammation after they have passed through the vascularendothelium. Alternatively, these mediators could act directly orindirectly on the vascular endothelium of the dermis to cause leakageleading to edema and/or the attraction and adhesion of circulatinginflammatory cells. Thus, there are multiple G-protein and otherpolyisoprenyl-protein mediated signaling responses between keratinocytesand inflammatory responding cells, which may provide multiple potentialtargets where AFC could act to reduce inflammation. The topical deliveryroute has the major advantage of giving AFC nearly direct access to thesite of inflammation. This avoids pharmacokinetic problems, such as drugdilution, major organ drug catabolism, and binding to serum components.

Example 1 Polyisoprenyl-Protein Inhibitor Compound AFC in an AcetoneCarrier Suppresses TPA-Elicited Edema in the Murine Ear Acute ContactIrritation Model

In order to assess the effects of the AFC inventive composition forreducing edema in the mouse ear model, an established model of dermalinflammation, was used. (See Carlson, R. P., et al., Modulation of mouseear edema by cyclooxygenase and lipoxygenase inhibitors and otherpharmacologic agents. Agents Actions, 1985. 17(2): p. 197-204; Kuehl, F.A., Jr., et al., Role of prostaglandin endoperoxide PGG2 in inflammatoryprocesses. Nature, 1977. 265(5590): p. 170-3; Trancik R J, L. N.,Evaluation of topical nonsteroidal anti-inflammatory agents, in Modelsin Dermatology, L. Maibach, Editor. 1985, Karger. p. 35-42; andTramposch, K. M., Skin Inflammation, in In Vivo Models of Inflammation,M. L. Morgan D W, Editor. 1999, Birkhauser Verlag. p. 179-204.)

The standard agents for initiating inflammation are the phorbol ester,tetradecanoylphorbol acetate, (TPA) and arachidonic acid (AA). TPAproduces a greater and more prolonged neutrophil infiltration responsethan AA (See Rao, T. S., et al., Comparative evaluation of arachidonicacid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermalinflammation. Inflammation, 1993. 17(6): p. 723-41.) TPA-inducedinflammation is the preferred agent and was used for this example.

A. Dose Response Curve for Irritant.

A dose response range for TPA, a compound known to induce edema, wasdetermined. TPA produces an increase in edema (ear swelling) thatreaches a maximum at 6 hrs.

Increasing concentrations of TPA dissolved in acetone were applied withthe aid of a micropipetter onto the right ear of each of the five 6-8week old, male Swiss Webster mice used in this analysis. Ten microliterswere spread evenly onto the inner and outer surfaces using the pipettetip. The mice were then returned to their cages. The contralateral earwas treated only with acetone. After 5.5 hours, the mice were sacrificedand 6 mm punches were taken from each ear and weighed. Edema responsewas expressed as a percent increase in the treated ear's weight over theuntreated ear. The dose response curve, as well as an ED₅₀ value, wasdetermined using the Lichtfield method (Lichtfield J T W. F., Asimplified method of evaluating dose-effect experiments, Journal ofPharmacology and Experimental Therapeutics, 1948, 96: P. 99-113).

As seen in FIG. 1, the increase in ear weight depends on TPA dose from0.25 to 1.75 μg/20 μl, reaching a maximum increase of approximately 150%of the acetone-treated ear. This experiment identified doses between1.5-2.0 μg/20 μl as suitable to use in eliciting edema in future testsof anti-inflammatory agents.

B. Polyisoprenyl-Protein Inhibitor Compound AFC in an Acetone Carrier,Itself, is not an Irritant.

A range of from 5 mg to 32 mg AFC, a polyisoprenyl-protein inhibitorcompound, was mixed with 20 μl acetone to produce an inventive AFCcomposition. Each concentration was applied with the aid of amicropipetter onto the right ear of each of six mice so that 10 μl ofeach of the concentrations of the AFC inventive compositions wereapplied to an inner ear surface and 10 μl was applied to an outer earsurface of the right ear. The AFC inventive compositions were spreadevenly with a pipette tip. Each contralateral ear was treated with onlyacetone in the same manner. The mice then were returned to their cages.After 5.5 hours, mice were sacrificed and 6 mm punches were taken fromeach ear and weighed. Edema response was expressed as the percentincrease in the treated ear's weight over the untreated (acetone,vehicle only) ear.

As shown in FIG. 2, AFC in acetone alone had no effect on the edemaresponse. The AFC inventive compositions had no effect on the ear punchbiopsy weight at a dose up to 32 mg/20 μl. AFC did not induce edema onits own at doses 60 fold greater than doses having efficacy againstchemically-induced edema. This finding suggests an excellent safetyprofile for AFC.

C. Result of AFC Inventive Composition on TPA-Induced Edema.

In order to assess the effects of the inventive composition onTPA-induced edema, 2 μg of TPA in 20 μl acetone was applied with the aidof a micropipetter onto both ears of each of 6 mice. The mice werereturned to their cages. Fifteen minutes later, increasingconcentrations of AFC in 10 μl of acetone were applied to the inside andoutside surfaces of the right ears as described above. 20 μl of anacetone vehicle was applied similarly to the left ear of each mouse asan internal negative control. After treatment, the mice were returned totheir cages for 5.5 hours. The mice were sacrificed by cervicaldislocation. The ears were immediately removed at their base and a 6 mmdiameter punch biopsy was taken from the center of each ear. The earpunch was weighed on an analytical balance for edema measurements asdescribed above. The ability of the various concentrations of AFC toinhibit TPA-induced edema was assessed by determining the difference inweight between the AFC-treated ear and the acetone (vehicle)-onlytreated ear over the increase in ear punch weight induced by TPA.

When AFC is tested in this acute inflammation mouse-ear assay, AFCreduces acute chemically induced inflammation significantly. Theinventive composition reduced the TPA-induced ear weight increase in adose dependent manner (FIG. 3). The inventive composition resulted in amaximum 80% reduction in edema. The ED₅₀ of the inventive AFCcomposition was approximately 0.44 mg/20 μl for TPA-induced edemainhibition.

Example 2 AFC Inhibits TPA-Induced Neutrophil Infiltration in Mice

A. TPA induces neutrophil infiltration in mice.

Acute contact irritants such as TPA can also induce dermal infiltrationof neutrophils. This may or may not be independent of the reduction ofedema, as: 1) the maximum neutrophil response is delayed relative themaximal edema response; 2) some irritants will induce edema independentof neutrophil infiltration; and 3) some of the known anti-inflammatoryagents reduce one, but not the other. (See Rao, T. S., et al.,Comparative evaluation of arachidonic acid (AA)- andtetradecanoylphorbol acetate (TPA)-induced dermal inflammation.Inflammation, 1993. 17(6): p. 723-41.) We sought to determine iftopically applied AFC would affect neutrophil infiltration in responseto acute topical irritation produced by TPA.

Neutrophil-Infiltration Assay:

Swiss Webster male mice (n=6) were treated with 1 μg/20 μl of TPA asdescribed above in order to assess whether or not TPA induced neutrophilinfiltration. Acetone was used as a control. TPA was administered asdescribed above. The mice were returned to their cages for 24 hrs toallow neutrophil infiltration, then sacrificed by cervical dislocation.The ears were immediately removed for punch biopsy, and punches werefixed for subsequent histological analysis and MPO enzymatic assay.

MPO Assay:

This assay measures myeloperoxidase, (“MPO”) which is packaged in theprimary granules of mature granulocytes including the neutrophil. Thus,the amount of MPO in the ear is proportional to the number ofinfiltrating neutrophils.

MPO enzyme activity of the ears was assayed using the technique detailedby Griffiths and coworkers (1988). To conduct the assay, each ear washomogenized in 1.0 ml of cetyltrimethylammonium bromide buffer for 5 secusing a Pro 200 tissue blender (Pro Scientific, Inc., Oxford, Conn.) atsetting 5. These samples were then centrifuged for 5 minutes at 15,000rpm in a 5415 Eppendorf microcentrifuge. Triplicate 20 microliteraliquots of supernatant were added to 200 microliters of reactionmixture (1.25 ml 1M Potassium Phosphate, 4,175 mg o-dianisidinedihydrochloride and 5 μl of 1% peroxide in a final volume of 25 ml).Absorbance at 450 nm was then measured at room temperature at three 60second intervals using Bio-Kinetics Reader EL 312E (Bio-TekInstruments). Activity, which was determined by a Bradford assay of thehomogenate (BioRad Protein Assay, BioRad Laboratories, Inc. Hercules,Calif.) was expressed as units MPO per mg tissue +/−standard error.

Neutrophil Counting Assay:

Ear punches buffered in 10% formalin in PBS at ambient temperature for aminimum of 24 hrs. were sectioned and stained with Hematoxilin & Eosin(“H&E”). The number of neutrophils, identified by their multilobularnuclei, in 6 randomly 100× magnified fields distributed along the lengthof the ear were manually counted. The results are expressed as theaverage number per field for each ear.

B. AFC Inhibits TPA-Induced Neutrophil Infiltration.

Inventive AFC compositions were used also to assess efficacy in thereduction of dermal neutrophil infiltration. (See Rao, T. S., et al.,Comparative evaluation of arachidonic acid (AA)- andtetradecanoylphorbol acetate (TPA)-induced dermal inflammation.Inflammation, 1993. 17(6): p. 723-4 for a discussion regarding therelationship between edema and neutrophil infiltration and the effect ofknown anti-inflammatory agents on these variables.)

Two micrograms of TPA in 20 μl of acetone was applied onto both ears ofeach mouse to induce neutrophil infiltration. After 15 minutes, varyingconcentrations of AFC in acetone were applied to the right ear of eachmouse. After 24 hours, the mice were sacrificed. The ears were removedand the efficacy of AFC on neutrophil infiltration was assessed by anMPO assay and histological analysis.

1. MPO Analysis

The results showed that AFC acts to reduce neutrophil infiltration in adose dependent manner when neutrophil infiltration is measured by an MPOanalysis. When AFC was tested in the Neutrophil-Infiltration Assay, itwas found to have no inflammation activity of its own. The data indicatethat AFC produced over an 80% inhibition of TPA-induced increases in MPOactivity and had an ED₅₀ of 0.065 mg/20 μl (FIG. 4).

2. Neutrophil Counts:

This histological analysis demonstrated the efficacy of AFC insuppressing dermal neutrophil infiltration in response to acute contactirritation. As seen in FIG. 5, the presence of neutrophils in the TPAalone treated ears was clearly observed 24 hours after treatment.Essentially no neutrophils were observed in the ears that were notexposed to TPA. In the ears pretreated with TPA and then treated withvehicle or AFC, the numbers of neutrophils were comparable betweenvehicle plus TPA-treated ear and ears treated with TPA alone. Asubstantial reduction of neutrophils can be observed in the AFC treatedear.

Upon counting the neutrophils, (FIG. 6) 1.0 mg/20 μl of AFC produced astatistically significant 80% reduction in dermal neutrophils producedin response to acute contact irritation by TPA. (Statisticalsignificance was calculated using a Student's paired t-test).

C. The Effect of AFC on Neutrophils is Time Dependent

The effectiveness of AFC treatment at various times before and after TPAapplication was assessed using MPO as a measure of neutrophilinfiltration. In this example, both ears of six mice were treated with a1 μg/20 μl dose of TPA in acetone. The right ear was then treated with 1mg/20 μl AFC inventive composition at various times before and after TPAapplication, while simultaneously treating the contralateral ear withacetone.

The results show the efficacy of AFC treatment prior to, simultaneouswith, or after exposure of skin to TPA (FIG. 7). There was a gradualdecrease in MPO activity with time at which AFC was applied after TPAapplication, the steroid dexamethasone showed a similar time dependence.Thus, it can be anticipated that AFC will act like steroids in reducingestablished inflammatory conditions.

These results support a wide range of possible cosmetic andpharmaceutical applications for AFC.

Example 3 The AFC Inventive Composition does not Exhibit SystemicEffects

The effect of AFC on TPA induction of neutrophil MPO activity wascompared with two other agents representing different classes ofcommonly used anti-inflammatories that inhibit inflammation bymechanisms different from AFC. These included dexamethasone, a steroid,and indomethasone, a non-steroid anti-inflammatory drug, which targetscycloxygenases. The action of AFC in this model was, therefore, comparedto that of dexamethasone and indomethasone. Each of these agents weretested using the same protocols used to test AFC.

As shown in FIGS. 8B and 8C, when the concentration of dexamethasone andindomethasone is increased, the contralateral vehicle-treated ear showsincreasing inhibition of MPO activity, reflective of inhibition ofneutrophil infiltration. This is evidence that topically applieddexamethasome and indomethasone are entering the circulation andexerting a systemic effect with increasing effective local doses. WithAFC, no effect was seen on the vehicle-treated ear (FIG. 8A). Topicallyapplied AFC, even at its highest effective local doses is not enteringthe circulation and, therefore, has no systemic effect in the mousemodel.

Example 4 Effect of an AFC and Acetone Composition on Arachadonic AcidInduced Edema and Arachadonic Acid-Induced Neutrophil Infiltration

Aracadonic acid (“AA”), another standard agent that is routinely used asa contact irritant in the mouse ear model to assay the effectiveness ofboth steroidal and nonsteroidal anti-inflammatory agents, is themetabolic precursor for a number of lipoxygenase and cyclooxygenaseproducts. Its mechanism of action and, thus, the signaling pathways itactivates, differ from those activated by topically applied TPA. AAproduces a more rapid edema than TPA that peaks at 1 hr afterapplication. There is minimal histologically observable neutrophilinfiltration in response to AA, but an increase in MPO can be detected.Experience has shown that effectiveness against cyclooxygenase activatedinflammation in this model is less predictive of effectiveness againsthuman inflammatory diseases than effectiveness against TPA activatedinflammation.

The effect of the inventive compositions on arachidonic acid(AA)-inducedinflammation was assayed using the same protocols as above, but with thefollowing modifications. AA was applied to both ears at 4 mg/40 μlacetone. The ears were harvested at 1 hr to measure edema, the maximumresponse time, and at 5 hr for inflammatory neutrophil infiltration asmeasured by an MPO assay.

The AFC inventive composition, prepared as described above, is lesseffective in reducing granulocyte infiltration induced by AA than TPA.It has 50% of the activity of TPA and a 10 fold higher ED₅₀ (FIG. 9).

Example 5 AFC Inventive Composition Visibly Reduces TPA-Induced Erythema

For this example, both ears of a mouse were treated with a 1 μg/20 μldose of TPA in acetone. After 1 hour, the right ear was treated with 1mg/20 μl of inventive AFC composition and the left ear was treated withacetone alone. The photo was taken 23 hours later using a Nikon D70digital camera. We have observed an effect of the AFC inventivecomposition on TPA-induced erythema (FIG. 10).

Example 6 AFC Inventive Compositions Reduce Inflammation in Humans whenPre-Applied

An irritant was applied to the middle of the upper back of a humansubject using a 0.2 ml 20% SDS solution and a Hill-Top Chamber patchwith Webril pad. AFC, at a concentration of 140 mM in aqueousformulation, was pre-applied to patch areas 1a and 1b (FIG. 11). Patches1a and 2a were removed after 2 hours, while patches 1b and 2b wereremoved after 2 hours and 30 minutes. High levels of irritation werevisible in patch sites 2a and 2b. Site 1a showed normal skin while 1bshowed a mild response. These results show that the inventivecomposition can reduce or prevent inflammation when human skin isexposed to an irritant.

Example 7 The Effect of AFC on Chronic Irritation in Mice

The effectiveness of the inventive compositions against establishedchronic irritation is assayed using a modification of the technique ofStanley P L et al., Mouse skin inflammation induced by multiple topicalapplication 12-O-tetradeconoyphorbol-13-acetate. Skin Pharmacol. 1991,4: p 262-271. (1991), Both ears of each mouse are treated with TPA inacetone, as above, in a series of 5 applications on the mornings of days0, 2, 4, 7, and 9. The treated ear receives the inventive compositionscontaining AFC and acetone, in series of three paired applications, suchthat it is applied 6 hr apart on days 7, 8 and 9. Punches of the earsare taken the afternoon of the tenth day and prepared, as above, for theedema assay and the infiltration of neutrophils. Total granulocyteinfiltration is assayed by measuring MPO activity. Macrophageinfiltration is determined immunocytologically using the MOMA-2antibody. Hydrocortisone, which is known to reduce inflammatory edemagranulation infiltration and microphage infiltration, is used as apositive control. The results will show that AFC in acetone reduceschronic edema and neutrophil number in mice.

Example 8 The Effect of the AFC Inventive Composition on Delayed-TypeHypersensitivity

The mouse ear model, described above, is modified to assay the effect ofanti-inflammatory agents in an immune based inflammation model (SeeTramposch, K. M., Skin Inflammation, in In Vivo Models of Inflammation,M. L. Morgan D W, Editor. 1999, Birkhauser Verlag. p. 179-20 andChapman, J. R., Z. Ruben, and G. M. Butchko, Histology of andquantitative assays for oxazolone-induced allergic contact dermatitis inmice. Am J Dermatopathol, 1986. 8(2): p. 130-8). In this model, asensitizing dose of dinitrofluorobenzene (“DNFB”) 1-3% in acetone isapplied topically according to a modification of the method by Back etal. (See Back, O. and T. Egelrud, Topical glucocorticoids andsuppression of contact sensitivity. A mouse bioassay ofanti-inflammatory effects. Br J Dermatol, 1985. 112(5): p. 539-45 andBailey, S. C., et al., A novel contact hypersensitivity model forrank-ordering formulated corticosteroids. Inflamm Res, 1995. 44 Suppl 2:p. S162-3) to the shaved bellies of mice to elicit an immune response.Mice are challenged on day 5 with 40 μl of 0.5-1% DNFB to each ear. TheAFC inventive compound is applied either 0.5 hr before or 15 min afterthe challenge to one ear and the vehicle is applied to the other ear.The ears are assayed for edema or neutrophil infiltration 5 hr later.Dexamethasone is used as a positive control. Five days later, the earsare challenged topically with a dose of DNFB insufficient to producecontact irritation. Simultaneously, cell infiltration studies areinitiated. Initially, there are more neutrophils than macrophages. By48-72 hrs, macrophages become the predominant population. Noinflammatory response is seen. The inventive AFC composition is,therefore, effective in reducing both edema and neutrophil infiltration.

1-90. (canceled)
 91. A topical composition comprising: at least onepolyisoprenyl-protein inhibitor compound present in the amount of about0.01% to about 50%, wherein the at least one polyisoprenyl-proteininhibitor compound comprises a compound of formula 1:

or pharmaceutically acceptable salts and esters thereof, wherein R¹ isalkyl of 1 to 3 carbon atoms; R² is —COX; wherein X is —OH, —OCH₃, —NH₂,—NHR⁴, —N(R⁴)₂ or halogen; R³ is a straight or branched chain alkyl of10 to 25 carbon atoms or a straight or branched chain alkenyl of 10 to25 carbon atoms; R⁴ is an alkyl of 1 to 25 carbon atoms; and a carrierselected from the group consisting of: water, ethanol, isopropanol,acetone, and combinations thereof.
 92. The topical composition of claim91, wherein R¹ is methyl, R² is COOH, and R³ is farnesyl.
 93. Thecomposition of claim 91, wherein R¹ is methyl, X is OCH³, and R³ isfarnesyl.
 94. The composition of claim 91, further comprising a retinoidselected from the group consisting of: vitamin A, retinol, retinal,retinyl palmitate, retinoic acid, tretinoin, iso-tretinoin, andcombinations thereof.
 95. The composition of claim 91, furthercomprising an alpha-hydroxy acid selected from the group consisting of:glycolic acid, lactic acid, tartaric acid, malic acid, citric acid, andcombinations thereof.
 96. The composition of claim 91, furthercomprising titanium oxide, zing oxide, benzoyl peroxide, fluorouracil,resorcinol, salicylic acid, or a mixture thereof.
 97. The composition ofclaim 91, wherein the topical formulation is in the form of a powder, anoil, a cream, a gel, or a bandage.
 98. The composition of claim 91,wherein the carrier is selected from the group consisting of: amoisturizing agent, a pH adjusting agent, a deodorant agent, athickener, a solubilizing agent, a penetration enhancer, ananti-irritant, a colorant, a surfactant, and combinations thereof. 99.The composition of claim 91, further comprising an active ingredientselected from the group consisting of: a protective agent, an emollient,an astringent, an irritant, a keratolytic agent, a sun screening agent,a sun tanning agent, an antibiotic agent, an antifungal agent, anantiviral agent, an antiprotozoal agent, an anti-acne agent, ananesthetic agent, a steroid anti-inflammatory agent, a non-steroidalanti-inflammatory agent, an antipruruitic agent, an ant-oxidant agent, achemotherapeutic agent, an anti-histimine agent, a vitamin, a hormone,an anti-dandruff agent, an anti-wrinkle agent, an anti-skin atrophyagent, a sclerosing agent, a cleansing agent, a caustic agent, ahypo-pigmenting agent, and combinations thereof.
 100. A cosmeticcomposition for reducing inflammation in humans when applied to a skinsurface of a human, the cosmetic composition comprising: at least onepolyisoprenyl-protein inhibitor compound comprising a compound offormula 1:

or pharmaceutically acceptable salts and esters thereof, wherein R¹ isalkyl of 1 to 3 carbon atoms; R² is —COX; wherein X is —OH, —OCH₃, —NH₂,—NHR⁴, —N(R⁴)₂ or halogen; R³ is a straight or branched chain alkyl of10 to 25 carbon atoms or a straight or branched chain alkenyl of 10 to25 carbon atoms; R⁴ is an alkyl of 1 to 25 carbon atoms; and a carrierselected from the group consisting of: water, ethanol, isopropanol,acetone, and combinations thereof.
 101. The cosmetic composition ofclaim 100, wherein the at least one polyisoprentyl-protein inhibitor isN-acetyl-5-farnesylcystein (“AFC”) and wherein the AFC is present in anamount of from about 0.01% to about 50% of the cosmetic composition.102. The cosmetic composition of claim 100, wherein the composition isin the form of a powder, an oil, a cream, a gel, or a bandage.
 103. Thecomposition of claim 101, further comprising a retinoid selected fromthe group consisting of: vitamin A, retinol, retinal, retinol palmitate,retinoic acid, tretinoin, iso-tretinoin, and combinations thereof. 104.The composition of claim 101, further comprising an alpha-hydroxy acidselected from the group consisting of: glycolic acid, lactic acid,tartaric acid, malic acid, citric acid, and combinations thereof. 105.The composition of claim 101, further comprising titanium oxide, zingoxide, benzoyl peroxide, fluorouracil, resorcinol, salicylic acid, ormixtures thereof.
 106. The composition of claim 101, wherein the topicalformulation is in the form of a powder, an oil, a cream, a gel, or abandage.
 107. The composition of claim 101, wherein the carrier isselected from the group consisting of: a moisturizing agent, a pHadjusting agent, a deodorant agent, a thickener, a solubilizing agent, apenetration enhancer, an anti-irritant, a colorant, a surfactant, andcombinations thereof.
 108. The composition of claim 101, furthercomprising an active ingredient selected from the group consisting of: aprotective agent, an emollient, an astringent, an irritant, akeratolytic agent, a sun screening agent, a sun tanning agent, anantibiotic agent, an antifungal agent, an antiviral agent, anantiprotozoal agent, an anti-acne agent, an anesthetic agent, a steroidanti-inflammatory agent, a non-steroidal anti-inflammatory agent, anantipruruitic agent, an ant-oxidant agent, a chemotherapeutic agent, ananti-histimine agent, a vitamin, a hormone, an anti-dandruff agent, ananti-wrinkle agent, an anti-skin atrophy agent, a sclerosing agent, acleansing agent, a caustic agent, a hypo-pigmenting agent, andcombinations thereof.
 109. A method of promoting healthy skin in anindividual, the method comprising: topically applying to a surface of ahuman in need thereof, an effective amount of at least onepolyisoprenyl-protein inhibitor compound present in an amount of fromabout 0.01% to about 50%, wherein the at least one polyisoprenyl-proteininhibitor compound comprises a compound of formula 1:

or pharmaceutically acceptable salts and esters thereof, wherein R¹ isalkyl of 1 to 3 carbon atoms; R² is —COX; wherein X is —OH, —OCH₃, —NH₂,—NHR⁴, —N(R⁴)₂ or halogen; R³ is a straight or branched chain alkyl of10 to 25 carbon atoms or a straight or branched chain alkenyl of 10 to25 carbon atoms; R⁴ is an alkyl of 1 to 25 carbon atoms; and a carrierselected from the group consisting of: water, ethanol, isopropanol,acetone, and combinations thereof.
 110. The method of claim 109, whereinthe at least one polyisoprentyl-protein inhibitor isN-acetyl-5-farnesylcystein (“AFC”).